Liquid dosage form mainly includes.

 

• Liquid Dosage Forms

• . Liquid dosage form mainly includes: • solution dosage forms • suspension dosage forms • emulsion dosage forms 

• . SOLUTION

• . Physicochemical definition • A solution is a homogenous onephase system consisting of two or more components. • The solvent, or mixture of solvents, is the phase in which the dispersion occurs, and the solute is the component which is dispersed as molecules or ions in the solvent.

• . –In general the solvent is present in the greater amount, but there are several exceptions Example, syrup BP contains 66.7% w/w of sucrose as the solute in 33.3% w/w of water as the solvent. –For most pharmaceutical solutions the solvent system in likely to be liquid and the solute will be either a liquid or a solid. Solutions of gases in liquids are characteristics of aerosols. 

• . –Solutions are also called molecular dispersions. –The solution should be able to pass in semi-permeable membranes • The solution should not be visible in electron microscope as a separate solute and solvent

• . • Advantages of solutions as an oral dosage forms: •Liquids are easier to swallow than solids and are therefore particularly acceptable for pediatric and geriatric use. •A drug must usually be in solution form before it can be absorbed. • If it is administered in the form of solution, the drug is immediately available for absorption. 

• . •Therefore, the therapeutic response is faster than if using a solid dosage form. → They have fast onset of action. •A solution is a homogenous system and therefore the drug will be uniformly distribute throughout the preparation. (In suspensions or emulsions formulations uneven dosage can occur as a result of phase separation on storage).

• . •Irritation is reduced by the administration of a solution of a drug because of the immediate dilution by the gastric content (esp. of GI irritant drugs like Aspirin).

• . Disadvantages –Liquids are bulky and therefore inconvenient to transport and store. If the container should break the whole of the product is immediately and irretrievably lost –The stability of ingredients in aqueous solution is often poorer than is formulated as tablets or capsules, particularly if susceptible to hydrolysis. short shelf-life.

• . –Solutions often provide suitable media for the growth of MOs and may therefore require the incorporation of preservatives. –Accurate dosage depends on the ability of the patient to use a 5ml spoon or a volumetric dropper.

• .– The taste of a drug, which is usually unpleasant, is always more pronounced when in solution than in a solid form. –Solution can, however, easily be sweetened and flavored to make them more palatable.

• . There are two types of solution preparations based on the solvent used: 1. Aqueous solution • Water is the most widely used vehicle for pharmaceutical products •Physiological compatibility & lack of toxicity •High dielectric constant

• . • Types of Pharmaceutical water: •Potable water: freshly drawn from the main system and which is suitable for drinking •Purified water BP: Freshly boiled and cooled immediately before use to destroy MOs that might be present •Water for injection: sterile water for parentral products

• . »Water/ethanol is commonly used. »Other, sorbitol, glycerol, propylene glycol, and syrups. » For example, water/propylene glycol (blend) is used to improve the solubility of co-trimoxazole.

• . • PH control:  large numbers of drugs are either weak acids or weak bases, and therefore their solubility in water can be influenced by the pH of the system. - The solubility of a weak base can be increases by lowering the pH of its solution, whereas the solubility of a weak acid is improved by an increase in pH. 

• . • In controlling the solubility of drugs in this way, it must  ensured that the chosen pH does not conflict with other product requirements. • For example, the chemicals stability of a drug may also depend on pH • This may also be true for other ingredients, esp. colors, preservatives, and flavors.   

• . • Solubilization: The solubility of a drug that is normally insoluble or poorly soluble in water can often is improved by the addition of surfactants. • Complexation: in some cases it may be possible to interact a poorly soluble drug with a soluble material to form a soluble macromolecular complex. 

• . • As most complexes macromolecular, however, they tend to be inactive, being unable to cross lipid membranes. • It is therefore essential that complex formation is easily reversible, so that the free drug is released during or before contact with biological fluids.

• .• Chemical modification: it involves mostly producing drugs in salt form. - Examples include the synthesis of the sodium phosphate salts of hydrocortisone, prednisolone and betamethasone. 

• . • The water soluble chloramphenicol sodium succinate has no antibacterial activity of its own but is suitable for parentral administration as a solution in order to obtain high blood levels, after which it is converted back to the less soluble active base 

• . 2. Non-aqueous solution:  this is especially important for slow release preparations. It is essential that, in choosing a suitable solvent, its toxicity, irritancy, and sensitizing potential are taken into account, as well as its flammability, cost, stability and compatibility with other exipients. 

• . • There is a greater choice of solvents available for inclusion into products for external application than those for internal use and that for parentral products the choice is limited even further. • Most widely used solvents in pharmaceutical preparations are: –Fixed oils of vegetable origin: - these are non-volatile oils that consist mainly of fatty acid esters of glycerol

• . –Alcohols: - ethyl alcohol is the most widely used solvent in this class, particularly for external application. –Polyhydric alcohols: - example. Propylene glycol (which is often used in conjunction with water or glycerol as a cosolvent). –Dimethylsulphoxide –Ethyl ether –Liquid paraffin

• . • Other formulation additives 1. Buffers: - these are materials, which dissolved in a solvent, will enable the solution to resist any changes in pH should an acid or an alkali is added. –The choice of suitable buffer depends on the pH and buffering capacity required. – It must be compatible with other excipients and have low toxicity. 

• . –Most pharmaceutically acceptable buffering systems are based on carbohydrates, citrates, gluconates, lactates, phosphates and tartarates. –Borates can be used for external application, but not to mucous membranes or to abrade skin. 

• . –As the pH of most body fluids is 7.4, products such as injections, eye drops and nasal drops should, in theory, be buffered at this value to avoid irritation. –Many body fluids themselves, however, have a buffering capacity and, when formulating low volume intravenous injections or eye drugs, a wider pH range can be tolerated.

• .• This is useful when choosing a pH that is physiologically acceptable for a drug whose optimum stability, solubility and /or bioavailability may depend on different pHs

• . 2. Density modifiers: • it is rarely necessary to control density of a solution except when formulating    spinal anesthetics • Solutions of lower density than CSF will tend to rise after injection and those of higher density will fall. Dextrose is mostly used.

• . 3. Isotonicity modifiers: • solutions for injection, for application on mucous membranes and large-volume solutions for ophthalmic use must be made iso-osmotic with tissue fluid to avoid pain and irritation. - Dextrose and sodium chloride are commonly used. • Isotonicity adjustments can only be made after the addition of all other ingredients, because each ingredient will contribute to the overall osmotic pressure of a solution.

• . 4. Viscosity enhancement: • it may be difficult for aqueous-based topical solution to remain in place on the skin or in the eye for any significant time because of their low viscosities. • To counteract this effect, low concentration of gelling agents can be used to increase the apparent viscosity of the product. • Examples include povidone, hydroxyethylcellulose and carbomer.  

• . 5. Preservatives: •when choosing a suitable preservation it must be ensured that. –Adsorption of the preservation onto the container from the product does occur, and –Its efficacy is not impaired by the pH of the solution or by interaction with other ingredients.

• . • Microorganisms form an integral part of our environment. • They are present in the air that we breath, the food that we eat and the water that we drink. • Some MOs indogenous to the body are present in considerable numbers. • They constitute up to one third of the dry weight of faces

• . • In this situation it’s apparent that both raw materials and final medicines will contain MOs unless specific measures are adopted to exclude them. • The preparation of sterile medicaments is a killed and expensive procedure demanding sophisticated equipments, skilled personnel and a controlled working environment.   

• . –To produce all medicines to such a standard would have a high cost. –Factors to considered: •The source and incidence of MOs in drugs and medical preparations •The consequences of such contamination both for the stability of medicine and for the health of the pt.

• .– Source of contamination »Air »Personnel »Building »Raw materials »Water »equipments

• . –There are two strategies to control microbial contamination 1. First and most important is to minimize the access of MOs from the sources 2. To formulate the final product so as to be hostile to MOs, normally by addition of preservatives.

• . 6. Reducing agents and antioxidants: •The decomposition of pharmaceutical products by oxidation can be controlled by the addition of reducing agents, such as sodium metabisulphat, or antioxidants such as butylated hydroxyanisole or butylated hydroxytolune

• . 7. Sweetening agents: •Law molecular weight carbohydrates, and in particular sucrose, are traditionally the most widely used sweetening agents. •sucrose has the advantage of being colorless, very soluble in water, stable over a pH range of about 4-8 and, by increasing the viscosity of fluid preparations will impart them a pleasant texture in the mouth

• . • It will mask the taste of both salty and bitter drugs and has a soothing effect on the membrane of the throat (Esp. for children) • Polyhydric alcohols such as sorbitol, manitol and to the less extent glycerol are also possessing sweetening power and included in preparations for diabetic use, whereas sucrose is undesirable.

• . • Artificial sweeteners can be used in conjunction with sugars and alcohols to enhance the degree of sweetness, or on their own in formulations for patients who must restrict their sugar intake. • Only about six artificial sweeteners are permitted for oral use within the European Union, the most widely used being sodium and calcium salts of Saccharin  

• .• Both exhibit high water solubility and are chemically and physically stable over a wide pH ranges. • The disadvantage of these agents is their tendency to impart a bitter or metallic after taste; due to this they are prepared with sugars.   

• . 8. Flavors and Perfumes • The simplest use of sweetening agent may not be sufficient to render palatable product containing a drug with a particular unpleasant taste. • In many cases, therefore, a flavoring agent can be included. • This is particularly useful in pediatric formulations.    

• .• Flavoring and perfuming agents can be obtained from either natural or synthetic sources. • Natural products include: - Fruit juices - Aromatic oils such as peppermint and lemon, herbs and spices, and - Distilled fraction of these

• .• They are available as concentrated extracts, alcoholic or aqueous solutions, syrups or sprit, and are particularly widely used in the manufacture of product for extemporaneous use. • Children in general, prefer fruity tastes and smells, whereas adults choose flowery odors and acid taste.   

• .

• 9. Colours • Once a suitable flavor has been chosen, it is often useful to include a color association with that flavor in order to improve the attractiveness of product. • Another reason for the inclusion of color is to enable easy product identification, particularly of poisonous materials. • For example, to differentiate between the many types of antiseptic solutions used in hospitals for the disinfection of skin, instruments, syringes, etc.    

• .TYPES OF PHARMACEUTICAL   SOLUTIONS

• . 1. Liquids for cutaneous application: lotions, liniments, paints and colloidions a. Lotions: can be formulated as solution, and are designed to be applied to the skin without friction. • They may contain humectants, so that moisture is retained on the skin after application of the product, or alcohol, which evaporates quickly, imparting a cooling after effect and leaving the skin dry.

• .b. Liniments: are intended for massage into the skin and can contain such ingredients as methyl salicylate or camphor as counterirritants. 

• . c. Paints: are liquid preparations for application to the skin or mucous membranes in small amount, and are usually applied with a small brush. • The solvent is normally alcohol, acetone or ether, which evaporates quickly leaving a film on the skin that contains the active ingredient. • A viscosity modifier such as glycerol is often added to ensure prolonged contact with the skin. 

• . d.Colloidions: are similar preparations which, after evaporation of the solvent, leave a tough, flexible film that will seal small cuts or hold a drug in intimate contact with the skin. • The film former is usually pyroxylin (nitrocellulose) in an alcohol/ether or alcohol/acetone solvent blend.

• . 2. Ear preparations: Also known as otic or aural products, these are simple solutions of drugs in either water, glycerol, propylene glycol or alcohol/water mixtures for local use, and include antibiotics, antiseptics, cleansing solutions and wax softeners. • They are applied to the external auditory canal as drops, sprays, or washes.  

• .3.Irrigations: are sterile, large volume aqueous-based solutions for the cleansing of body cavities and wounds. • They should be made isotonic with tissue fluid. 4. Eye preparations: are semi-volume sterile liquids designed to be instilled on to the eye ball or within the conjunctival sac for a local effect.

• . 5. Mouthwashes and gargles: are aqueous solutions for the prevention and treatment of mouth and throat infections and can contain antiseptics, analgesics and/or astringents. • They are usually diluted with warm water before use. e.g.  Potassium chlorate and phenol gargle, thymol. Glycerin gargle.

• . 6. Nasal products: are formulations as small-volume solutions in an aqueous vehicle. • Because the buffering capacity of nasal mucus is low, formulation at a pH of 6.8 is necessary. • These can be antibiotics, antinflammatories, decongestants.

• . Formulation includes: • Active drug • Vehicle (water) • Preservation • Viscosity modifying agents • Buffers 

• . 7. Solutions used orally: a. Spirits: • Are alcoholic or aqueous – alcoholic solutions of volatile substance –Aromatic substance  + alcohol –Aromatic substance + Hydro alcoholic solvent • Most are used as flavoring agents but a few have medicinal value. • Excess addition of water leads to salting out of the oil.

• .

• b. Syrups: • These are concentrated aqueous solutions of sugars such as sucrose. • Sucrose in water at 85% (w/v)                   -simple syrup • Syrup + flavoring agent                            -flavorant syrup

• . Components of syrup In addition to water and the medicinal agent, syrup mainly contains –sugar and sugar substituent's –flavorings –colorants – preservative Note that: - simple syrup doesn’t need preservation because it contains small proportion of water.

• .C. Elixirs • Elixirs are clear , sweetened, hydro alcoholic solutions intended for oral use, and are usually flavored to enhance their palatability • Non-medicated elixirs are employed as vehicles. • Medicinal elixirs are employed for the therapeutic effect of the medicinal substance they contain. 

• . • Constituents of Elixir –Drug as in the case of medicated elixir –Alcohol and water –Co-solvents such as glycerin and propylene glycol –Sweetening agents  e.g. sucrose, saccharin –Flavoring agents (increase palatability) –Coloring agents (enhance appearance)

• .

• Note that:• The proportion of alcohol present in elixirs varies widely since the individual components of the elixirs have different water and alcohol solubility characteristics • Each elixir requires a specific blend of alcohol and water to maintain all of the components in solution.

• .• Elixirs containing over 10to 12 % of alcohol are usually selfpreserving and do not require any preservation.

• . Comparison of syrup and elixirs Compared to syrups: • Elixirs are usually less sweet and less viscous because they contain a lower proportion of sugar –Hence elixirs less effective than syrups in masking the taste of medicinal substances.

• .• Because of their hydroalcoholic character, elixirs are better able than aqueous syrups to maintain both watersoluble and alcohol –soluble components in solution. • Because of their stable characteristics and the ease which they are prepared, elixirs are preferred over syrups. • In short, elixirs (are): - more clear 

• .More stable - less viscous      } compared to syrup - Less sweet                                             - Easy to prepare - require more preservative    

• .D. Linctuses • Linctus is a viscous preparation, usually prescribed for the relief of cough. • It normally consists of a simple solution of the active agent in a high concentration of sucrose, often with other sweetening agents. 

• . • The syrup content has a demulcent action on the mucous membranes of the throat. • For diabetic use the sucrose is usually replaced by sorbitol and/or synthetic sweeteners 9. Parentral products  • These are sterile products for injection or infusion into the body.

• . 10. Rectal preparations (Enemas) • An enema is an oily or aqueous solution which is administered rectally. • Enemas may be used rectally either for systemic effect or local effect or both. • Used for –Cleansing –Diagnosis –Therapeutic purposes.

• . 11. Miscellaneous solutions • Aromatic waters –Aromatic waters are near-saturated aqueous solutions of volatile oils or other aromatic or volatile substances. –Aromatic waters are used as a vehicle in oral solutions and their flavoring properties.

• .Example • Peppermint water • Anise water                  both have carminative properties • Chloroform water—acts as preservative

• . 2. Extracts, infusions and tincture- are terms for concentrated solutions of active principles from animal or vegetable sources. a. Infusions: are prepared by extracting the drug using 25% alcohol, but without the application of heat. b. Traditionally these preparations are then diluted 1:10 in the final product.

• . b. Extracts: are similar products that are then concentrated by evaporation c.Tinctures: are alcoholic extracts of drugs but are relatively weak compared with extracts

• . General Methods of preparation of solutions 1. simple solution method 2. chemical reaction method 3. extraction method 

• . Simple solution method • This method involves simple addition of solute to the solvent Example: - For readily soluble solutes e.g. Nacl, sugar, CaCl2 etc • Dissolve the solids in about ¾ of the solvent in flask, stir, transfer to a measuring cylinder and adjust the volume.

• . For those size reduction is necessary; e.g. ferrous sulfate •Triturate them in a mortar with about ¾ of the solvent •Transfer to a measure; rinse the mortar with the remaining solvent. •Add to the measure.

• . Chemical reaction method • This involves reaction of two or more substances in a suitable solvent. • The substances dissolved are not active when used alone. e.g.  Formaldehyde solutions prepared by oxidation of methanol in a catalyst i.e. Methanol     oxidation      Formulation Catalyst

• .• Formaldehyde solution = formalin • Formalin is used as antiseptic and disinfectant (for inanimates ) Extraction • This involves dissolving out certain components in plant parts or certain animal tissues usually by allowing a long time contact b/n the solvent and the component to be extracted.

• . SUSPENSIONS

• .

• Definition • A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. • The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent.  

• . • The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use • The insoluble solid substance which is dispersed in the solvent is called the disperse Phase or internal phase • The solvent in which the solid disperses is called the continuous phase or external phase.

• .

• Classification 1. Based on General use • Oral suspension • Externally applied suspension • Parenteral suspension 2. Based On Proportion of Solid Particles • Dilute suspension (2 to10%w/v solid) • Concentrated suspension (50%w/v solid) 

• . 3. Based On Electrokinetic Nature of Solid Particles • Flocculated suspension • Deflocculated suspension 4. Based On Size Of Solid Particles • Colloidal suspension (< 1 micron) • Coarse suspension (>1 micron) • Nano suspension (10 ng) 

• . Features Desired In Pharmaceutical Suspensions • The suspended particles should not settle rapidly and sediment produced must be easily re-suspended by the use of moderate amount of shaking. • It should be easy to pour yet not watery and no grittiness. • It should have pleasing odor, color and palatability. 

• .• Good syringeability. • It should be physically, chemically and microbiologically stable. • Parenteral/Ophthalmic suspension should be sterilizable. Applications –Suspension is usually applicable for drug which is insoluble or poorly soluble. E.g. Prednisolone suspension 

• . –To prevent degradation of drug or to improve stability of drug. E.g. Oxytetracycline suspension –To mask the taste of bitter or unpleasant drug. E.g. Chloramphenicol palmitate –Suspension of drug can be formulated for topical application e.g. Calamine lotion –Suspension can be formulated for parentral application in order to control rate of drug absorption. 

• . –Vaccines as an immunizing agent are often formulated as suspension. E.g. Cholera vaccine –X-ray contrast agents are also formulated as suspension. E.g. Barium sulphate for examination of alimentary tract –To prolong the action of the drug (because in suspension formulation the active drug is released very slowly)

• .

• Types of Suspensions • Depending on the nature of the disperse phase, we have four types of suspensions. 1. Suspensions containing diffusible solids • Some insoluble powders are light and easily wettable ,hence they readily mix with water and on shaking diffuse evenly through the liquid for long enough to ensure even distribution in each dose. • Such substances are known as diffusible or dispersible solids

• .Examples  Calcium carbonate  Light kaolin  Light kaolin (natural)  Light Magnesium Carbonate  Magnesium Trisilicate

• .2. Suspensions containing Indiffusible Solids • Indiffusible solids will not remain evenly distributed in a vehicle long enough to ensure uniformity of dose. • The simplest way of correcting this problem is to increase the viscosity of the vehicle by adding a thickening agent 

• .

• Examples Used Internally Used Externally  Aspirin  Calamine  Chalk  Hydrocortisone  Aromatic chalk powder     Sulphur, precipitated  Phenobarbitone  Triamcinolone Acetonide  Succinylsulphathiazole  Zinc oxide  Sulpha dimidine

• . 3. Suspensions containing poorly wettable solids • Some substances e.g. Sulphur and hydrocortisone, are both in-soluble in water and poorly wetted by it. • When preparing simple aqueous dispersions it is difficult to disperse clumps, and the foam produced on shaking is slow to subside because it is stabilized by the film of unwettable solid at the liquid/air interface 

• . • To ensure satisfactory wetting, the interfacial energy between the solid and liquid must be reduced • This may be achieved by adding a suitable wetting agent which is adsorbed at the solid liquid interface in such a way that the affinity of the particles for the surrounding medium is increased, while the interparticular forces are decreased  Examples: Alcohol in tragacanth mucilage : Glycerin and glycerols in sodium  alginate 

• . 4. Suspensions of precipitate-forming liquids • Some liquid preparations contain resinous matter that is precipitated on addition to water Examples Compound benzoin Tincture Benozin Tincture Myrrh Tincture

• . • With Myrrh Tincture the resin is precipitated in diffusible form unless the preparation contains appreciable quantities of electrolytes • With the others, the precipitated resin adheres to the side of the container and forms non-dispersable clots in the liquid • To prevent this, a protective colloid is dispersed in the vehicle before the tincture is added

• . Flocculated and Deflocculated Systems • Sometimes suspensions are classified as flocculated and deflocculated systems • Whether or not a suspension is flocculated or deflocculated depends on the relative magnitudes of the forces of repulsion and attraction between the particles • In a deflocculated system the dispersed particles remain as discrete units and, because the rate of sedimentation depends on the size of each unit, settling will be slow

• . • The supernatant of a deflocculated system will continue to remain cloudy for an appreciable time after shaking, due to the very slow settling rate of the smallest particles in the product, even after the larger ones have sediment • The slow rate of the settling prevents the entrapment of liquid within the sediment, which thus becomes compacted and can be very difficult to redisperse

• . • This phenomenon is also called caking or claying, and is the most serious of all the physical stability problems encountered in suspension formulation • The aggregation of particles in a flocculated system will lead to a much more rapid rate of sedimentation because each unit is composed of many individual particles and is therefore larger The nature of the sediment of a flocculated system is also quite different from that of a deflocculated one 

• .• The structure of each aggregate is retained after sedimentation, thus entrapping a large amount of the liquid phase • In a flocculated system the supernatant quickly becomes clear, as the large flocks that settle rapidly are composed of particles of all sizes.

• . • In summary, deflocculated systems have the advantage of a slow sedimentation rate, thereby enabling a uniform dose to be taken from the container, but when settling does occur the sediment is compacted and difficult to redisperse

• • Flocculated systems from loose sediments which are easily redispersible, but the sedimentation rate is fast and there is a danger of an inaccurate dose being administered: also the product will look inelegant

• Relative properties of Flocculated and De flocculated particles in suspensions

• Deflocculated Flocculated 1. Particles exist in suspension as separate entities. 1. Particles form loose aggregates. 2.Rate of sedimentation is slow, As each particle settles Separately and particle size is Minimal. 2. Rate of sedimentation is high, as particles settle as a flock, which is a collection of particles. 3.Asediment is formed slowly 3.Asediment is formed rapidly. 4.The sediment eventually becomes very closely packed, due to weight of upper layers, of sedimenting material Repulsive forces between particles are overcome and a hard cake is formed that is difficult to redisperse 4.The sediment is packed loosely. Particles do not bond tightly to each other and a hard, dense cake does not form. The sediment is easy to redisperse, so as to reform the original suspension

• 5. The suspension has a pleasing appearance, as the suspended material remains suspended for a relatively long time The supernatant also remain cloudy, even when settling is apparent

• 5. The suspension is somewhat unsightly, due to rapid sedimentation and the presence of an obvious, clear supernatant region

• Fig1; sedimentation behavior of flocculated and deflocculated systems

• . Particle size control: it is first necessary to ensure that the drug to be suspended is of a fine particle size prior to formulation This is to ensure: Slow rate of sedimentation of the suspended particles Prevent gritty texture of the product ( >5μm) Ease of administration (parentral products) no polydispersion

• .• Eventhough the particle size of a drug may be small when the suspension is first manufactured, there is always a degree of crystal growth that occurs on storage, particularly if temperature fluctuations occur • Different polymorphic forms of a drug may exhibit different solubility, the metastable state being the most soluble

• .• Conversion of the metastable form, in solution, to the less soluble stable state, and its subsequent precipitation, will lead to changes in particle size • Solvents: Water or other solvents can be used based on the type of the material used

• Other additives: 1. Wetting agents: to ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid. Most widely used wetting agents are:  Surface-active agents: - are usually organic compounds that are amphiphilic, meaning they contain both hydrophobic groups (their "tails") and hydrophilic groups (their "heads"). Therefore, they are soluble in both organic solvents and water

• . • Most surfactants are used at concentration of up to about 0.1% as wetting agents and include, for oral use, the polysorbates (Tweens) and sorbitan esters (spans) • For external application, sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extracts can also be used • The disadvantages of using this type of wetting agents include: excessive foaming and the possible formation of a deflocculated systems, which may not be required

• . Hydrophilic colloids: - these materials include acacia, bentonite, tragacanth, xanthan gum and cellulose derivatives, and will behave as protective colloids by coating the solid hydrophobic particles with a multi-molecular layer – This will impart a hydrophilic character to the solid and so promote wetting Solvents: - materials such as alcohol, glycerol, and glycols, which are water miscible, will reduce the liquid/air interfacial tension. – The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles, so enabling wetting to occur by the dispersion medium.   

• . 2. Flocculating agents: in many cases, after the incorporation of non-ionic wetting agents a suspension will be found to be deflocculated, either because of the reduction in solid/liquid interfacial tension, or because of the hydrated hydrophilic layer around each particle forming a mechanical barrier to aggregation. - The use of anionic surfactant to wet the solid could produce either a flocculated or a deflocculated system, depending on any charge already present on the particles

• . • If particles are of opposite charge to that of the surfactant then neutralization will occur • If a high charge density is imparted to the suspended particle deflocculation will be the resulted. • Some of the flocculating agents are:

• . o Electrolytes: the addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur • The most widely used electrolytes include the sodium salts of acetates, phosphates and citrates, and the concentration chosen will be that which produces the desired degree of flocculation • Care must be taken not to add excessive electrolyte or charge reversal may occur on each particle, so forming, once again, a flocculated system

• . o Surfactants: ionic surface active agents may also cause flocculation by neutralizing the charge on each particle, thus resulting in deflocculated systems E.gs. Alkyl benzene sulfonate, fatty acid salts, Benzalkonium chloride (BAC), Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfate salts 

• . o Polymeric flocculating agents: starch, alginnates, cellulose derivatives, tragacanth, carbomers and silicates are examples • Their inner branched-chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state 

• . 3. Viscosity modifiers: the following materials are those most widely used for the modification of suspension viscosity; polysaccharides: these includes; –Acacia -natural material often used as a suspending agent for extemporaneously prepared suspensions – Acacia is not a good thickening agent and its value as a suspending agent is largely due to its action as a protective colloid –B/c of its stickness it is rarely used in preparation for external application

• . –Tragacanth-this product will form viscous aqueous solutions. It can be used both for internal and external products. –Alginates –alginic acid and its salts have suspending properties similar to those of tragacanth. Sodium alginate is the most widely used material. –Starch – starch is rarely used on its own as a suspending agent but is one of the constituents of compound tragacanth powder.

• . Water soluble cellulose:  several cellulose derivatives are available that will disperse in water to produce viscous colloidal solutions suitable for use as suspending agents. –Methylcellulose (celacol, Methocel) – is a semi-synthetic polysaccharide and produced by methylation of cellulose. Depending on the degree o f methylation and chain length there are several grades. The longer the chain, the more viscous is its solution.

• .– Hydroxyethylcellulose (Natrosol) – has hydroxyethyl instead of methyl groups attached to the cellulose chain. It has the advantage of being soluble in both hot and cold water and will not gel on heating. –Carmellose sodium ( sodium caroxymethylcellulose) –Microcrystalline cellulose

• .• Hydrated silicates: there are three important materials within this classification –Bentonite –Magnesium aluminum silicate – hectorite • Carbomers (carboxypolymethylene) • Colloidal silicon dioxide

• . Formulation of Pharmaceutical    Suspensions

• . • Suspension formulation requires many points to be discussed • A perfect suspension is one, which provides content uniformity • The formulator must encounter important problems regarding particle size distribution, specific surface area, inhibition of crystal growth and changes in the polymorphic form

• . • The formulator must ensure that these and other properties should not change after long term storage and do not adversely affect the performance of suspension • Choice of pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled at the time of formulation

• . Formulation Components • The various components, which are used in suspension formulation, are as follows : 

• Components Function

• API Active drug substances Wetting agents They are added to disperse solids in continuous liquid phase.

• Flocculating agents They are added to flock the drug particles

• Thickeners They are added to increase the viscosity of

• suspension.

• Buffers and pH adjusting agents They are added to stabilize the suspension to

• a desired pH range.

• Osmotic agents They are added to adjust osmotic pressure

• comparable to biological fluid.

• Coloring agents They are added to impart desired color to

• suspension and improve elegance.

• Preservatives They are added to prevent microbial growth. External liquid vehicle They are added to construct structure of the final suspension

• . Generally there two main methods of suspension formation: A. Precipitation Methods: - less widely used, it involves suspending an insoluble drug by precipitating it from a solution ♦ Organic solvent precipitation –precipitating the drug from a water-miscible solvent on addition of water, a soluble form of the drug is dissolved in a suitable vehicle, sterilized by filtration and then precipitated to form a suspension ♦ Precipitation effected by changing of the pH of the medium (solution) - for weak acid or base ♦ Double decomposition

• .B. Dispersion Method The most important problem with suspension formulations is sedimentation

• . Packaging of Suspensions

• .• Due to the world wide emergence of the drug regulations and increasing sophistication in variety of dosage forms and development of new packaging materials, today pharmacist must aware of wide range of packaging material that relates directly to the stability and acceptability of dosage forms

• . • For example, to optimize shelf life industrial pharmacist must understand inter-relationship of material properties, while the retail pharmacist must not compromise with the storage of the dosage forms. • So because of that labeling and storage requirements are important for both patient as well as pharmacist

• .• Pharmaceutical suspensions for oral use are generally packed in wide mouth container having adequate space above the liquid to ensure proper mixing • Parenteral suspensions are packed in either glass ampoules or vials • Generally glass and various grades of plastics are used in packaging of suspension

• . The specific FDA regulation for the drug states that: “Container, closure, and other components of the packaging must not be reactive, additive or absorptive to the extent that identity, strength, quality, or purity of the drug will be affected”

• . Storage Requirements (Labeling) Shake well before use Do not freeze Protect from direct light (For light sensitive drugs) 

• .

• EMULSION

• .Definition • Emulsions are mixtures of two immiscible liquids (water and oil) uniformly dispersed through out the other. • It can also be defined as a dispersion in which the disperse phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible. • An emulsion may be defined as two immiscible liquids, one of which is finely subdivided and uniformly distributed as droplets throughout the other.  

• . • The dispersed liquid is known as the internal or discontinuous phase where as the dispersion medium is known as the external or continuous phase • The dispersed liquid or internal phase usually consists of globules of diameters down to 0.1 μm which are distributed within the external or continuous phase

• . How do immiscible liquid, disperse into one another • When two immiscible liquids are in contact there exists at the separating surface, or interface, a tension or force that retards dispersion of one liquid in the other • Vigorous shaking may break one liquid into globules that become distributed throughout the other • This condition is only temporary as separation quickly takes place on standing

• . • If a third substance is added it may concentrate as a film at the interface, consequently, the globules of dispersed liquid may remain indefinitely distributed in the other liquid instead of coalescing to form a separate layer • A substance that can act in this manner is called an emulsifying agent, emulgent or emulsifier • A stable emulsion thus must contain at least three components :  The dispersed phase  The dispersion medium and  The emulsifying agent

• .

• Applications of Emulsions

• . • Emulsions have a wide range of uses, including:  Oral, rectal and topical administration of oils and oils soluble drugs Formulation of oil and water-soluble drugs together To enhance palatability of oils when given orally by masking both taste and oiliness Increasing absorption of oils and oil soluble drugs through intestinal walls

• . Intra muscular injections of some watersoluble vaccines provide slow release and therefore a greater antibody response and longer-lasting immunity Total parenteral nutrition makes use of a sterile oil-in-water emulsion to deliver oily nutrients intravenously to patients

• .Type of Emulsion • Emulsions may be: - W/o emulsion - O/w emulsion - Multiple emulsions (W/O/W or O/W/O) - Micro emulsion

• . Identification of Emulsion Types • Several simple methods are available for distinguishing between O/w and w/o emulsions • The most common of these involve: 1. Miscibility tests (Dilution Test) –An emulsion will only mix with a liquid that is miscible with its continuous phase –Therefore an o/w emulsion is miscible with water and a w/o emulsion is miscible with an oil

• . 2. Conductivity Test • Systems with an aqueous continuous phase will conduct electricity, whilst systems with an oily continuous phase will not 3. Staining (dye solubility) Test • Water-soluble and oil-soluble dyes are used, one of which will dissolve in, and color the phase in which it is soluble •

• . Choice of emulsion type • W/o and o/w emulsions are the most common type of emulsions Emulsions of the type o/w are administered orally: To mask the taste or oiliness of medicinal oils To improve absorption of oil- fine subdivision is believed to increase the amount and rate of absorption in the intestine

• . • Emulsions of the type o/w are superior to w/o emulsions when used for external purpose • These are because: They rub into the skin more readily They are easily removed by washing Evaporation of the aqueous phase causes cooling They do not significantly interfere with the heat lose b/c the oil phase is discontinuous

• . Emulsions of w/o on the other hand: Are easier to spread evenly When used on non-weeping surfaces prevent dehydration and restore suppleness of the skin  A preparation with this property is said to be emollient (having the quality of softening or soothing the skin)

• .

• Stability Problems in Emulsion

• .• A stable emulsion is one in which the globules:Retain their initial character (i.e. mean size and size distribution) and Remain uniformly distributed throughout the continuous phase

• . Common problems with emulsions are: Phase inversion • This is the process in which an emulsion changes from one type to another say o/w to w/o • The most stable range of disperse phase concentration is 30 – 60% • Addition of substances which alter the solubility of an emulsifying agent may-also cause phase inversion • The process is irreversible

• .

• Creaming • The term creaming is used to describe the aggregation of globules of the disperse phase at the top or bottom of the emulsion • The process is reversible and gentle shaking redistributes the droplets throughout the continuous phase • Creaming is undesirable because it is inelegant and inaccurate dosing is possible if shaking is not through • Also, creaming increases the likelihood of coalescence of globules and therefore, breakdown of the emulsion due to cracking

• . Cracking or breaking • Cracking is the coalescence of dispersed globules and separation of the disperse phase as a separate layer • It is an irreversible process and redispersion cannot be achieved by shacking

• . Emulsifying agents and the HLB system –Emulsifying agents help the production of a stable emulsion by reducing interfacial tension and then maintaining the separation of the droplets by forming a barrier at the interface –Most emulsifying agents are surfaceactive agents (are wetting agents that lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids)

• . Emulsion type is determined by the solubility of the emulsifying agent If the emulsifying agent is more soluble in water then water will be the continuous phase and an o/w emulsion will be formed If the emulsifying agent is more soluble in oil, oil will be the continuous phase and a w/o emulsion will be formed

• . The ideal emulsifying agent is: • Colorless • Odorless • Tasteless • Non-toxic • Non-irritant And • able to produce stable  emulsions at low concentrations

• . Classification of emulsifying agents (EAs) • There are many types of emulgent available, but for convenience they can be divided into two main classifications 1. Naturally occurring EAs, which includes : –Polysaccharides e.g. acacia, Tragacanth, starch, pectin –Semi-synthetic polysaccharides e.g. Methylcellulose, carboxymethyl/cellulose –Sterol-containing substances e.g. bees wax, wool fat and wool alcohols

• .2. Synthetic surfactants • There are four main categories of these materials, depending on their ionization in aqueous solutions: anionic, cationic, non-ionic and amphoteric

• .

• Anionic surfactants In aqueous solutions these compounds dissociate to form negatively charged anions that are responsible for their emulsifying ability They are widely used because of their cheapness They are only used for externally applied preparations, because of their toxicity They are incompatible with some organic and inorganic cations and with large organic cations They are generally stable at more alkaline PH E.g. Sodium stearate, calcium oleate, sodium lauryl sulphate

• .

• Cationic Surfactants In aqueous solutions these materials dissociate to form positively charged cations that provide the emulsifying properties They are sensitive to anionic surfactants and drugs They are usually quaternary ammonium compounds They are used in the preparation of emulsions for external use Emulsions formed by a cationic surfactant are generally stable at acidic PH The cationic surfactants also have antimicrobial activity E.g. Cetrimide, benzalkonium chloride

• .

• Non-ionic Surfactants • These agents do not dissociate either into positively or negatively charged species (in aqueous solutions) • These agents make up the largest group of surfactants • They are used to produce emulsions for both external and internal use • The non-ionic surfactants are compatible with both anionic and cationic substances • They are also highly resistant to PH change

• . • With these agents, the type of emulsion formed depends on the balance between hydrophilic and lipophilic groups which is given by the HLB (Hydrophilic Lipophilic Balance) E.g.  • Glycol and glycerol esters • Macrogol ethers and esters • Sorbitan esters And  • Polysorbates

• .Amphoteric Surfactants • This type possesses both positively and negatively charged groups, depending on the PH of the system • They are cationic at low PH and anionic at high PH • They are not widely used E.g. Lecithin

• .The HLB system • The HLB method is chiefly of value for non-ionic emulgents • Each emulsifying agent is given a number on the H.L.B. scale • High numbers indicate hydrophilic (lipophobic) properties • Low numbers indicate hydrophobic (lipophilic) properties

• H.L.B Range Application

• 3 – 6 Emulsifying agent (w/o)

• 7 – 9 Wetting agent

• 8 – 18 Emulsifying agent (o/w)

• 13 – 15 Detergent

• 15 – 18 Solubilising agent

• H.L.B. ranges and their applications

• . Other formulation additives:  Buffers: - may be necessary for: Maintaining chemical stability Controlling tonicity Ensuring physiological compatibility  Humectants: - to reduce the evaporation of the water from the surface of the skin after application • Glycerol • Polyethylene glycol and • propylene glycol 

• . Antioxidants  Flavors, colors and perfumes  Sweetening agents  Preservatives

• . Methods of emulsion preparation • In the small-scale extemporaneous preparation of emulsions, two methods may be used • They are:  1) Continental or dry gum method                          2) English method or wet gum method

• .

• Dry Gum Method • In this method the EA (usually acacia) is mixed with the oil before the addition of water • The method is also referred to as the “4: 2: 1” method because for every 4 parts (volumes) of oil, 2 parts of water and 1 part of gum are added in the preparing the initial or primary emulsion • In this method the acacia or other o/w emulsifier is triturated with the oil in a perfectly dry wedge wood or porcelain mortar until thoroughly mixed

• . • A mortar with a rough rather smooth inner surface must be used to ensure proper grinding action and the reduction of the globule size during the preparation of the emulsion • After the oil and gum have been mixed, the two parts of water are then added all at once, and the mixture is triturated immediately

• .• Other liquid formulatives ingredients that are soluble in or miscible with the external phase may then be added to the primary emulsion with mixing • Solids substances such as preservatives, stabilizers, colorants and any flavoring material are usually dissolved suitable volume of water and added as a solution to the primary emulsion

• .Wet Gum Method • By this method, the same proportions of oil, water and gum are used as in the continental or dry gum method but the order of mixing is different • Generally mucilage of the gum is prepared by triturating granular action with twice its weight of water in a mortar

• . • The oil is then added slowly in proportions and mixture is triturated to emulsify the oil • Then, as with the continental or dry gum method, the other formulative agents are added, and the emulsion is transferred to a graduate and made to volume with water